Antipsychotic drugs produce most of their clinical effects, both therapeutic and adversive, in a time-dependent manner which, depending upon the effect, can take days to years to develop. Using extracellular single unit recording and microiontophoretic techniques, we investigated the effect of chronic haloperidol (CHAL) treatment (0.5 mg/kg/day s.c. x 22d) on nigral dopaminergic (DA) neuronal activity. CHAL treatment resulted in an almost total absence of spontaneously firing nigral DA cells. Further studies suggested that CHAL treatment causes an increase in the activity of DA cells to the point that the great majority go into apparent tonic depolarization block. This effect appears to be mediated via striato-nigral feedback pathways. The effects of CHAL treatment on the spontaneous activity of rat caudate neurons were also determined suing extracellular single unit recording techniques. Two types of spontaneous potentials were observed: monophasic and biphasic. CHAL treatment increased the number of active monophasic potentials while it decreased the number of active biphasic units. Monophasic potentials also showed a supersensitivity to dopamine. These time-dependent changes in DA neurons and caudate cell activity may correlate with the development of clinical neurologic side-effects induced by neuroleptic treatment and provide a mechanism for their delayed onset.